DiscoveryBioMed, Inc. (DBM) has launched an innovative and automation-friendly drug discovery program to screen a collection of small molecular compounds on a human epithelial cell platform expressing physiologically relevant levels of the wild-type Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) to discover a new class of therapeutic drugs for secretory diseases. CFTR plays a critical role in the regulation of Cl- transport and fluid secretion such that hyperactivity of the CFTR Cl- channel results in uncontrolled fluid secretion. Two CFTR-mediated diseases, secretory diarrhea and Autosomal Dominant Polycystic Kidney Disease (ADPKD), are driven in part by chronically active CFTR. These diseases demand treatment options that are effective and readily available due to their widespread impact on public health. Diarrheal illnesses are a leading cause of death worldwide. Despite the accepted practice of oral rehydration therapy, the incidence of secretory infection remains alarmingly high;and, thus, there is a constant need to develop drugs that alleviate diarrheal symptoms. The need to find therapeutic options for ADPKD is even more urgent due to a complete lack of FDA-approved drugs available for the nearly 12.5 million people suffering from this kidney disease. DBM recognizes the severity of these clinical problems and has focused our drug discovery efforts in developing an innovative program that would not only provide possible therapeutic options for the aforementioned diseases, but would also allow for the mechanistic study of CFTR function in the pathogenesis of CFTR-mediated diseases, which is also currently limited. The novelty in this drug discovery program depends on the use of a biologically relevant human cell platform that expresses the disease-relevant target, wild-type CFTR. DBM embodies the philosophy of 'humanized'drug discovery to increase disease relevance while decreasing risk in advanced stages of de novo drug screening. It is this core principle that reflects DBM's unique angle, approach, and offering to the drug discovery space. For this SBIR Phase I application, DBM presents a series of methodical and focused steps that will aid in the successful completion of this proposal and are outlined by the following Milestones: 1) Develop and implement a novel drug discovery platform with human CFBE cells expressing wild-type CFTR to detect potent compounds inhibiting CFTR-mediated Cl- secretion, 2) Perform de novo HTS of 75,000 small molecular compounds for the discovery of novel CFTR inhibitors, 3) Validate putative hits as delineated by a robust Critical Path, 4) Establish physiological relevance for validated hits for ADPKD and secretory diarrhea, and 5) Perform chemoinformatics on validated hits for the identification of hit-to-lead chemical classes for drug candidate selection and deeper chemical profiling. As an added benefit, DBM has existing internal CF and ADPKD programs which provide a unique infrastructure of valuable expertise and resources to help accomplish all Milestones and projected goals. A preliminary proof- of-concept screen of >5% of the total compound library has been completed, where validated hits and compounds of interest are now being tested in advanced stages within the Critical Path. DBM seeks SBIR funds to deepen and accelerate this critical CFTR inhibitor drug discovery program.

Public Health Relevance

ADPKD and diarrheal diseases are two seemingly unrelated illnesses that are linked through a shared mechanism which results in chronically active and detrimental chloride and fluid secretion across afflicted epithelium. Together, these diseases kill more than 2.2 million people annually and represent major global health burdens. Diarrheal diseases are a leading cause of death worldwide, killing more young children annually than AIDS, malaria, and measles combined. ADPKD is a genetic disorder that causes an irreversible decline in kidney function. There are approximately 600,000 people suffering from ADPKD in the US alone. However, because this disease has a high incidence rate of up to 1 in every 1000 births, it is estimated to affect over 12.5 million people worldwide. At present, there is no cure or ADPKD, and treatment options are limited to alleviating secondary symptoms that arise from renal function impairment. The potential for a drug to target a common biological mechanism like CFTR-driven Cl- secretion for the treatment of two medically important secretory diseases is a cost effective way to have a broad impact on global health. Investing in drug discovery programs to help alleviate diarrheal and ADPKD disease progression would result in substantial savings to national health care programs. Discovery Bio Med is poised to bridge its resources and knowledge from existing internal CF and ADPKD programs, two areas of expertise that will aid in the discovery and maturation of drug candidates against secretory diseases like ADPKD and diarrheal illnesses.